Conjugate additions Mukaiyama Michael addition

MacMillan reported a short and effective synthesis of spiculisporic acid which elegantly exemplified his Mukaiyama-Michael addition of silyloxyfurans to a,P-unsatu-rated aldehydes [88], Robichaud and Tremblay augmented this in a formal synthesis of compactin [224], Within this report it was shown that low enantioselectivities were obtained in the conjugate addition to aCTolein. Use of p-silyl acrolein 177 circumvented this and gave butenohde 178 in 95% yield and 82% ee. Conversion of adduct 178 to the decaUn (179) in eight steps resulted in a formal synthesis (Scheme 71). 

As will be shown, the stereochemistry of Mukaiyama-Michael additions is in many instances insensitive to the stereochemistry of the silyl enol ether used. This method is potentially advantageous relative to the direct conjugate addition of ketone enolates when it is impossible to obtain the enolate or silyl enol ethers in a stereoisomerically pure form. 

Mukaiyama-Michael Addition, Mukaiyama-Michael Conjugate... 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates were obtained in greater than 10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone (Michael-Mukaiyama reaction). Further optimization of the stereoselectivity was achieved by the choice of the silyl substituents. The observed stereoselectivity is consistent with synclinal TSs for the addition of the crotyl silane reagents. 

Silylketene acetals and enolsilanes can also undergo conjugate addition to a,/ -unsaturated carbonyl derivatives. This reaction is referred to as the Mukaiyama-Michael addition and can also be used as a mild and versatile method for C-C bond formation. As shown in Scheme 8-34, in the presence of C2-symmetric Cu(II) Lewis acid 94, asymmetric conjugate addition proceeds readily, giving product with high yield and enantioselectivity.75... 

The elfectiveness of imidazolidinone of type 11 was confirmed by successful application to a broad range of chemical transformations, including cycloadditions, conjugate additions, Friedel-Crafts alkylations, Mukaiyama-Michael additions, hydrogenations, cyclopropanations, and epoxidations. A summary of these enantio-selective iminium catalyzed processes is provided by reaction subclass. 

The titanium(IV) chloride-catalyzed conjugate addition of enol silyl ethers (182) to (184) and (189 Scheme 30), and silyl ketene acetals, (191) to (194), to ot, 3-enones is die key feature in various synthetic strategies (Mukaiyama-Michael) (Scheme 31).78 79 In contrast to the earlier described enolate addition... 

Mukaiyama-Michael reaction1 (13, 339-340 14, 344-345). The conjugate addition of enol silyl ethers of optically active ketones to a,(i-enones catalyzed by trityl perchlorate can proceed with high diastereoselectivity. Thus the (Z)-enol silyl ether (2) of the ketone (R)-l reacts with enone 3 to give the 1,5-ketone 4 with high... 

Conjugate additions. Cyclopentaneacetic esters are readily prepared by cyclization of -iodo-a,P-unsaturated esters. The Michael reaction of silyl ketene acetals with enones (and Mukaiyama aldol reaction) can be promoted by Sml,. " However, thermodynamic enolsilylation of carbonyl compounds under similar conditions is noted. 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

In some instances, particularly when a dependence of the stereochemistry on the double-bond geometry of either the acceptor or donor is observed, it appears likely that the stereochemistry-determining step is the initial conjugate addition. The stereochemical consequences of Lewis-acid-mediated additions of silyl enol ethers (116) and allylsilanes (117,118) have frequently been rationalized by open-extended transition states. Similar pathways seem likely with the Mukaiyama-Michael addition (vide infra) (77,79). 

Mechanistically, enamine and Lewis-acid-mediated conjugate additions are complex. The opportunity exists for the product-determining step to occur at a number of points and, without further study, the precise nature of the manifold is not entirely clear. In some enamine cases where the stereoselectivity likely results from the conjugate addition, a synclinal type transition state seems to be involved. With the Mukaiyama-Michael addition, some processes implicate an open-extended pathway. Despite the mechanistic uncertainties that remain, sufficient data are now available so that the stereochemistry in many cases can be anticipated by extrapolation. 

Michael reaction. Great activity is exhibited by Zn(OTf)2 for promoting the Mukaiyama version of the Michael addition involving the enol silyl ether of methyl a-diazoacetoacetate and conjugated cycloaUrenones. 

This reaction was first reported by Mukaiyama et al. in 1974. It is a Lewis acid-catalyzed Michael conjugate addition of silyl enol ether to o ,/3-unsaturated compounds. Therefore, it is generally referred to as the Mukaiyama-Michael reaction. Because this reaction is essentially a conjugate addition, it is also known as the Mukaiyama-Michael addition or Mukaiyama-Michael conjugate addition. This reaction is a mechanistic complement for the base-catalyzed Michael addition, j and often occurs at much milder conditions and affords superior regioselectivity. s Besides silyl enol ether, silyl ketene acetals are also suitable nucleophiles in this reaction.For the hindered ketene silyl acetals, the Lewis acid actually mediates the electron transfer from the nucleophiles to o ,/3-unsaturated carbonyl molecules.On the other hand, the Q ,j8-unsaturated compounds, such as 3-crotonoyl-2-oxazolidinone, alkylidene malonates, and a-acyl-a,/3-unsaturated phosphonates are often applied as the Michael acceptors. It has been found that the enantioselectivity is very sensitive to the reactant structures —for example, Q -acyl-Q ,j8-unsaturated phosphonates especially prefers the unique syn- vs anft-diastereoselectivity in this reaction. In addition,... 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

The oxonia-Cope rearrangement is also a key aspect of the Mukaiyama-Michael cascade reaction developed by Rychnovsky, which results in the formation of tetrahydropyran rings with high levels of stereoselectivity. As demonstrated in the example below, the Lewis acid promoted conjugate addition of enol ether 190 results in an intermediate oxocarbenium ion, formation of which is followed by Cope rearrangement. 

A reported diastereoselective synthesis of precursor A of vitamin D3 involved the use of 2-methylcyclopent-2-enone as starting material. The Mukaiyama-Michael conjugate addition of ketene acetal 269 in the presence of trityl hexachloroaniimonate afforded the adduct 270. The lateral chain was introduced, according the procedure of Tsuji, by the treatment of crude 270 with allyl carbonate and palladium dibenzylideneacetone " (Scheme 63). The expected product 271 was obtained in 63% yield from 269. Reduction of 271 with LAH afforded a mixture of diols that was selectively tosylated at the primary hydroxy group. The secondary hydroxy group was protected with the methoxymethyl group and further functional modifications afforded the lactone 272. The reaction of lithium dimethyl methylphosphonate with the lactone 272 completed the synthesis of the AB-des-cholestane derivative 273. 

Michael Reactions. Several reports highlighting utilization of the title reagent in Mukaiyama-type Michael reactions have now appeared. 3,4-Dihydro-Q -pyrones are obtained in quantitative yield from the reagent and a, -unsaturated ketones via a two-step sequence comprising conjugate addition followed by mercuric ion mediated cycUzation (eq 11). ... 

Conjugate addition of ketenesilyl acetals to a,P-unsaturated carbonyl compounds (Mukaiyama-Michael reaction) with Li Lewis acid has been widely investigated. When sterically less hindered ketenesilyl acetals are utilized, the reaction proceeded smoothly, even in catalytic systems (with LiCo(B9C2Hn)2 in CICH2CH2CI or LiCl04 in CH2CI2). On the other hand, in the case of more hindered ketenesilyl acetals, high concentration of LPDE is necessary to promote the reaction... 

Conjugate addition of nitroalkanes to a,P-unsaturated aldehydes in the presence of imidazolyl-imidazolidin-4-ones was described by Arvidsson and coworkers [92], In addition, silyl enol ethers of substituted acetophenones [93] or thioesters [94] react with a,P-unsaturated aldehydes under iminium-catalysis conditions in the sense of a Mukaiyama-Michael reaction (Scheme 4.24). Applications of this transformation can be found in the total syntheses of compactin [95] and homocitric acid lactone and its homolog [96]. 

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